Surgical implant comprising an anabolic and a corticosteroid

ABSTRACT

A surgical implant with a basic structure, preferably configured as an implant mesh, contains an anabolic steroid and a corticosteroid. The implant is preferably designed to release these active substances after implantation. It becomes incorporated rapidly and effectively, without any undesired scar contraction occurring.

The invention relates to a surgical implant (in particular an implantmesh) which, while permitting accelerated wound-healing, does notadditionally cause scar contraction.

After they have been implanted in the body, implants generate aforeign-body reaction which, following an inflammatory reaction, leadsto the formation of scar tissue. The foreign-body reaction triggers aformation of connective tissue around the implant, and, at a laterstage, this connective tissue further differentiates to a greater orlesser extent into scar tissue. Scar tissue is tighter than connectivetissue, which means that, in the course of said differentiation, thetissue draws together and the implant thus also contracts.

In the case of incisional hernias, a reduction of up to 80% in thesurface area of the implant is observed in the course of wound-healing.This “shrinkage” is due to the contraction of the formed scar tissuearound the implant. The reduction in the surface area of an implant meshcan lead to recurrences, particularly in the case of hernias.

The contraction depends on the quantity of implant used (pore width inthe case of meshes, weight) and on the surface characteristics ofimplant. The shrinkage observed in conventional polypropylene meshes isusually between 30% and 50% of the original surface area (Klosterhalfen,B., Junge, K., Hermanns, B., Klinge, U.: Influence of implantationinterval on the long-term biocompatibility of surgical meshes, Brit,. J.Surg., 89, 2002, 1043-1048; Klinge, U., Klosterhalfen, B., Müller, M.,Schumpelik, V.: Foreign body reaction to meshes used for the repair ofabdominal wall hernias, Eur. J. Surg., 165, 1999, 665-673), in ePTFEmeshes it is 30% to 50% (Klinge, U., Klosterhalfen, B., Müller, M.,Schumpelik, V.: Foreign body reaction to meshes used for the repair ofabdominal wall hernias, Eur. J. Surg., 165, 1999, 665-673), and in thepartially resorbable composite meshes sold by Ethicon, under the names“Vypro” and “Vypro II”, it is about 30% (Klinge, U., Klosterhalfen, B.,Müller, M., Schumpelik, V.: Foreign body reaction to meshes used for therepair of abdominal wall hernias, Eur. J. Surg., 165, 1999, 665-673) andunder 10%, respectively.

Various approaches are known for reducing the foreign-body reaction:

-   -   Changing the geometry of the mesh to give a smaller surface area        (hence fewer foreign bodies), for example by using        monolfilaments or larger pores (V. Schumpelik, Hernien,        published by Thieme Verlag, 4th edition, 1992, 10-11). Thus,        conventional polypropylene meshes have narrow pores and a large        weight per unit area, while the abovementioned “Vypro” meshes        are partially resorbable and have wide pores in the        non-resorbable area.    -   Modifying the surface of the implant material, for example        modification by physical methods (Plasma, Plasma        polymerization; B. Ratner (Ed.), Biomaterials science, an        introduction to materials science, 105 et seq.), modification by        chemical methods (B. Ratner (Ed.), Biomaterials science, an        introduction to materials science, 105 et seq.), for example        with PEO (Jenney, C. R., Anderson, J. M.: Effects of        surface-coupled PEO on human macrophage adhesion and foreign        body giant cell formation in vitro, J. Biomed. Mater. Res.,        44(2), 1999, 202-216), PVA (Matsuda, S. Se, N., Iwata, H.,        Ikeda, Y.: Evaluation of the antiadhesion potential of UV        cross-linked gelatin films in a rat abdominal model,        Biomaterials 23(14), 2002, 2901-2908); US 2002/0071855,        hyaluronic acid (WO 02/09792 A1) or by graft copolymerization        (directly or after activation) (B. Ratner (Ed.), Biomaterials        science, an Introduction to materials science, 105 et seq.), and        modification by coating the implant with a biocompatible layer,        for example by dip coating or spin coating.    -   Using what are called active implants (Drug Delivery Systems) in        which biologically active molecules are incorporated into the        implant, for example TGF-beta (O'Kane, S., Ferguson, M. W. J.:        TGF-beta in wound healing, Int. J. Biochem. Cell Biol., 29(1),        1997, 63-78) or TGF-alpha (Dixon, Fergusson: The effects of EGF,        TGF-alpha, TGF-beta, PDGF on murine palatal shelves in organ        culture, Arch. Oral. Biol., 37(5), 1992, 395-410). Such implants        release agents and are aimed at controlling the connective        tissue in a specific and oriented manner around the implant and        at generally reducing the foreign-body reaction, in order        thereby to counteract contraction.

It is known that corticcsteroids such as dexamethasone (Saarela, T.,Risteli, J., Kauppila, A., Koivisto, M.: Effect of short term antenetaldexamethasone administration on type I collagen synthesis anddegradation in preterm infants at birth, Acta Pediatr., 90(8), 2001,921-925) inhibit the synthesis of type I collagen and thus of stableconnective tissue (Anstead: Steroids, retinoids and wound healing, Adv.Wound Care, 11(6), 1998, 277-285); at fairly high dosages the sameapplies to vitamin D3 and its derivatives (Czarnetzki, B. M.: Vitamin D3in dermatology: a critical appraisal, Dermatologica, 178(4), 1989,184-188). In addition, they inhibit the contraction of type I collagenin the course of wound-healing (Greiling, D.: 3-alpha-25dihydroxyvitaminD3 rapidly inhibits fibroblast induced collagen gel contraction, J.Invest. Dermatol., 106(6), 1996, 1236-1241; Van Story-Lewis, P. E.,Tenenbaum, H. C.: Glucocorticoid inhibition of fibroblast contraction ofcollagen gels, Biochem. Pharmacol., 35(8), 1986, 1283-1286). Anabolicsteroids, by contrast, increase the synthesis of type I collagen(Falanga, V., Greenberg, A. S., Zhou, L., Ochoa, S. M., Roberts, A. B.,Falabella, A., Yamaguchi, Y.: Stimulation of collagen synthesis by theanabolic steroid stanozolol, J. Invest. Dermatol., 111(6), 1998,1193-1197; Demling, R. H.: Oxandrolone, an anabolic steroid, enhancesthe healing of a cutaneous wound in the rat, Wound Rep. Regen., 8(2),2000 97-102).

A combination of corticosteroids and anabolic steroids leads toincreased collagen production without simultaneous wound contraction(Hatz, Kelley, Ehrlich: The tetrachlordecaoxygen complex reverses theeffect of cortisone on wound healing, Plast. Reconstr. Surg., 84(6),1989, 953-959; Kim, C. S. et al.: The effect of anabolic steroids onameliorating the adverse effect of chronic corticosteroids on intestinalanestototic healing in rabbits, Surg. Gynecol. Obstet. 176(1), 1993,73-79).

Corticosteroids are also used as immunosuppressants, and anabolicsteroids for building muscle and in the treatment of osteoporosis.

The object of the invention is to make available a surgical implantwhich becomes incorporated rapidly and effectively but which does notcause undesired scar contraction.

This object is achieved by a surgical implant with the features of claim1. Advantageous embodiments of the invention are set out in thedependent claims.

The surgical implant according to the invention has a basic structureand comprises (at least) one anabolic steroid and (at least) onecorticosteroid. The basic structure is preferably designed with an arealconfiguration, and specifically preferably as an implant mesh, althoughit can also be in another form (see below). The implant is preferablydesigned to release the anabolic steroid and/or the corticosteroid afterimplantation.

With the implant according to the invention, it is possible, in additionto the primary support function of the implant, to achieve a localadministration of two active substances, namely an anabolic steroid anda corticosteroid, which act directly on the surrounding tissue. Theanabolic steroid increases and accelerates the formation of type Icollagen (synthesis of support tissue). The corticosteroid prevents thecontraction of the support tissue as this matures to scar tissue. Thus,firmer integration (more collagen) of the basic structure of the implantis achieved without contraction. The implant thus becomes rapidlyincorporated without reduction of its surface area. The accelerated andfirmer incorporation, without scar contraction, reduces the risk ofrecurrence.

The anabolic steroid and the corticosteroid exert a local action. It isthus possible to avoid the side effects which can arise in systemicadministration. After implantation, the implant according to theinvention can release the anabolic steroid and/or the corticosteroideither immediately or after a delay, and the release can also take placeover a long period of time. In this way, the stated effects are inducedin the region of the implant. The time pattern of the release of thesteroids can be predetermined by the way in which they are arranged inor on the basic structure. For example, the steroids can diffuserelatively quickly out of the pores of the basic structure if they arebound only in the surface of the latter via intermolecular forces. If,by contrast, the steroids are located in the inside of a resorbablepolymer, the time of release depends on the progress of the resorptionof the polymer.

The quantity of anabolic steroid and of corticosteroid in the implantaccording to the invention (expressed as absolute mass or in percent byweight relative to the weight of the basic structure) can vary over awide range, depending on the specific application, and can be determinedspecifically for the particular case. For the anabolic steroid, datafrom systemic use may serve as a starting point. For example, dependingon the steroid, administrations of between 0.5 μg/kg/day(fluoxymesterone) through 0.1 to 3 mg/kg/day (tibolone) up to 10mg/kg/day (testosterone) for prolonged periods (here in each caserelated to 1 kg bodyweight) or, for example, individual intramuscularinjections of 50 mg are known. For stanozolol, the natural serum level(plasma level) is approximately 10⁻⁸ M and the toxic dose is 10⁻⁴ M; inthis case the practical dose range extends from approximately 10⁻⁸ M toapproximately 10⁻⁵ M. For glucocorticoids, individual systemic doses of10 mg/kg/day and local doses in the wound area of 2 μg/day to 50 mg/day(depending on the preparation) are known. When transposing the systemicdose ranges to the implant, account must be taken of the local area ofaction (i.e. the lower weight of the body tissue in question) and thegenerally higher tolerance at the desired site of action.

For the basic structure, which largely determines the mechanicalproperties of the implant, very different forms can be considereddepending on the intended use. Apart from the areal implant structuresalready Mentioned (in particular implant meshes, preferably fortreatment of hernias), other examples are: three-dimensional structures,fleece-like structures, felts, blocks, porous structures, foams, cords,threads, and tapes, but also, for example, vessel prostheses end stents.Not least, combinations or composites of the aforementioned forms arealso possible.

The basic structure can be resorbable, non-resorbable or partiallyresorbable. It can include inorganic and/or organic material. Examplesof inorganic materials are: hydroxylapatite, calcium phosphates (e.g.dicalcium phosphate and octacalcium phosphate, but in particulartricalcium phcsphate and its modifications such as alpha-tricalciumphosphate and beta-tricalcium phosphate), mixed phosphates,non-resorbable glasses and resorbable glasses. So-called biologicalglasses of varying composition may also be considered. Examples oforganic materials are: polymers (non-resorbable or resorbable),reinforced polymers, pre-degraded resorbable polymers (e.g. a copolymerof glycolide and lactide in the ratio 90:10, whose duration ofresorption is shortened by pretreatment in a hydrolysis buffer),polylactides (e.g. poly-L-lactides and poly-D-lactides), polyglycolides,copolymers of glycolides and lactides, poly-p-dioxanone andpolycaprolactones, but also natural polymers such as celluloses (e.g.alginate, starch and derivatives thereof). The basic structure can, inprinciple, comprise several different materials.

For the anabolic steroid, examples which may be considered are tibolone,fluoxymesterone, stanozolol, nandrolone, nancrolone decanoate,nandrolone octydecanoate, and testosterone, and derivatives of thesesubstances. It is also conceivable to provide more than one anabolicsteroid so that the actions of the individual steroids can complementeach other.

Examples of corticosteroid are: cortisone, furacin, polysporin,methylprednisolone, dexamethasone and glucocorticoids. If necessary, aplurality of corticosteroids can be provided.

There are a great many possible ways of integrating the anabolic steroidand the corticosteroid into the basic structure or of arranging them ontop of the latter and, if appropriate, of connecting them to the basicstructure, optionally also so that the steroids are released in achronologically predetermined manner. For example, the steroids can beincluded in a coating of the basic structure. If the coating comprises aresorbable basic substance, the steroids are released in the course ofthe resorption process. Moreover, a steroid can be contained in theinside of the basic structure, for example in a basic structure made ofresorbable material. The release of active substances from spheres isdescribed in the literature (e.g. Matsumoto, J., Nacada, Y., Sakurai,K., Nakamura, T., Takahashi, Y.: Preparation of nanoparticles consistingof poly(L-lactide)-poly(ethylene glycol)-poly(L-lactide) and theirevaluation in vitro, Int. J. Pharm., 185(1), 1999, 93-101).

Coatings with the anabolic steroid and/or the corticosteroid can beapplied to the basic structure by spraying or by means of an immersionprocess, for example. If a steroid is to be introduced in the inside ofthe basic structure, suitable processes are, for example, swelling in asolvent with the steroid, diffusion processes, immersion processes (witha porous basic structure), shaping of the basic structure from asteroid-containing melt, and use of emulsions or supercriticial carbondioxide.

The anabolic steroid and/or corticosteroid can also be contained in arelease unit arranged or the basic structure, for example in a pelletwith a resorbable material as binder. Several coatings are alsoconceivable, e.g. including separate coatings for the individual activesubstances, or combined forms of the possibilities mentioned. Theseindividual variations care be used to influence or control the localaction and timing of the steroids.

The invention is explained in more detail below on the basis ofexamples.

EXAMPLE 1

An anabolic steroid and a corticosteroid are dissolved in a coatingsolution. A commercially available implant mesh for hernia repair isimmersed in a bath containing this solution and then removed from thelatter. After drying, the active substances remain in the surface of theimplant mesh serving as basic structure. After implantation of the mesh,the active substances are released and thereby exert their intendedeffect.

EXAMPLE 2

For a trial on rabbits, dexamethasone (0.1 mg/kg) and nandrolone (2mg/kg to 20 mg/kg) are combined in different ratios in acontrolled-release pellet made of a resorbable lactide/glycolidecopolymer. When implanted on a wound, this leads to acceleratedwound-healing with reduced wound contraction but the same stability ofthe wound (tear resistance of the newly formed skin). The pellet issuitable for integration into an implant.

EXAMPLE 3

A hernia mesh charged with anabolic steroid and corticosteroid as activesubstance is introduced using one of the standerd open or laparoscopictechniques and thus actively supports the healing of the defect inaddition to the stabilizing action of the implant mesh per se. Allapplications in contact with soft tissue are conceivable.

EXAMPLE 4

Stanozolol (0.5 μg/ml to 5 μg/ml) increases the synthesis of type Icollagen in human skin fibroblasts by a factor of 2 to 4.

Cortisone prevents fibroblast contraction (human, dermal) even at lowdoses (below 10⁻⁶ M)

EXAMPLE 5

A combination of cortisone and testosterone in a controlled-releasepellet accelerates wound-healing while maintaining the tear resistanceof the newly formed tissue, even in immunosuppressed rats.

EXAMPLE 6

To test a hernia mesh for preventing scar contraction, a tube made ofcolorless “Vicryl” yarn (“Vicryl”: copolymer of glycolide and lactide inthe ratio of 90:10, Ethicon, Germany) of 56 dpf (deniers per filament)with a diameter of 10 mm is produced on a Lucas circular knittingmachine.

This tube is coated in one stage by completely immersing it for about 2minutes in a bath containing the following:

-   -   5% by weight of glycolide/lactide copolymer (35% by weight of        glycolide, 65% by weight of lactide) with an intrinsic viscosity        of 0.4 dl/g to 0.8 dl/g    -   10% by weight of nandrolone    -   1% by weight of dexamethasone    -   dispersed in ethyl ethyl acetate (remainder % by weight)

The tube is then dried at 50° C. to 55° C. The coated tube is stored ina nitrogen atmosphere.

Efficacy is demonstrated in the rat model. Pieces measuring 1 cm inwidth and 5 cm in length are cut out from the tube and implanted underthe skin of a rat's back and then explanted after 7, 14, 21, 56 and 119days. After explantation, the remaining surface area of the respectivepiece is measured and the resulting scar tissue is tested for its tearresistance and type I collagen content. Pieces of uncoated “Vicryl” tubeand an uncoated “Vicryl” mesh (“Type 9,” Ethicon, fine-pore mesh) areused as control. The quantity of newly formed type I collagen in thecoated pieces is twice the quantity in the control. As a result, thetear resistance of the tissue also increases, with significantly lessscar contraction (measured on the basis or the remaining surface area ofthe respective piece).

EXAMPLE 7

In a two-stage process, a first coating with steroid (in this casestanozolol and cortisone) is applied to an uncoated “Vicryl” meshanalogously to Example 6. After drying, an additional layer is added ofthe coating polymer, (without steroid). The active substances aretherefore located farther away from the surface, so that afterimplantation they are retardedly released in the course of theresorption of the coatings.

EXAMPLE 8

Analogously to the tubers described in Example 6, a great many otherbasic structures can be equipped in the ways described In Examples 6 and7, for example:

-   -   meshes made of “Vicryl” (copolymer of glycolide and lactide in        the ratio 90:10, Ethicon),    -   meshes made of “Vypro” (composite of “Vicryl” and polypropylene,        Ethicon),    -   composite meshes mace of “Vicryl” and “Proncva”(“Pronova”:        mixture of polyvinylidene fluoride and a copolymer of vinylidene        fluoride and hexafluoropropene, Ethicon),    -   “Mersilene” meshes (polyester, Ethicon),    -   “Monocryl”-containing meshes (copolymer of glycolide and        epsilon-caprolactone, Ethicon),    -   mesh pouches made of “Vicryl”,    -   and other non-resorbable meshes,    -   tapes and cords, for example a woven polyester tape        (“Mersilene”, Ethicon) or made of other resorbable and        non-resorbable materials,    -   fleeces, needlefelts and felts made of “Vicryl” and/or        poly-p-dioxanone yarns,    -   vessel prostheses,    -   stents.

1. A surgical mesh comprising an anabolic steroid and a corticosteroid.2. (canceled)
 3. (canceled)
 4. (canceled)
 5. The surgical mesh accordingto claim 1, further comprising at least one of the substances selectedfrom the group consisting of hydroxylapatite, calcium phosphates,non-resorbable glasses, resorbable glasses, polymers, resorbablepolymers, reinforced polymers, pre-degraded resorbable polymers,polylactides, poly-L-lactides, poly-D-lactides, polyglycolides,copolymers of glycolides and lactides, poly-p-dioxanone,polycaprolactones, and celluloses.
 6. The surgical mesh according toclaim 1, wherein the anabolic steroid comprises at least one of thesubstances selected from the group group consisting of stanozolol,nandrolone, nandrolone decanoate, nandrolone octydecanoate,testosterone, tibolone, fluoxymesterone, and derivatives of theaforementioned substances.
 7. The surgical mesh according to claim 1,wherein the corticosteroid comprises at least one of the substancesselected from the group consisting of cortisone furacin, polysporin,methylprednisolone, dexamethasone, and glucocorticoids.
 8. The surgicalmesh according to claim 1, wherein the anabolic steroid and/orcorticosteroid is/are contained in at least one coating on the surgicalmesh.
 9. (canceled)
 10. The surgical mesh according to claim 1, whereinthe anabolic steroid and/or corticosteroid is/are contained in a releaseunit arranged on the surgical mesh.